AORTA, BRAIN AND KIDNEY STRUCTURE AND FUNCTION IN THE AGES-REYKJAVIK STUDY

描述(由申请人提供)：60岁后主动脉僵硬显著增加，并与心脏病、中风、认知障碍和肾脏疾病的风险增加有关。尽管已经确定了几个导致主动脉僵硬异常的危险因素，但从危险因素到主动脉功能障碍再到过高的压力脉动性和脑和肾脏下游损害的基本机制仍不完全清楚。主动脉僵硬和血压波动过大与微血管重构、肥厚和反应性受损有关，这可能导致终末器官损害。我们建议在年龄、基因/环境易感性-雷克雅未克研究(AGEs-Reykjavik)中对4000名参与者进行动脉血压测量和详细的脑部磁共振成像(MRI)，并对600名参与者进行主动脉和肾脏的MRI检查。我们对这一建议的假设有3个方面：1)主动脉弓近端管壁硬化和主动脉直径与血流不匹配是老年人过度压力脉动的主要来源；2)随之而来的脉压增加对小血管结构和功能有不利影响，表现为脑(脑血管输入阻抗)和肾脏(肾血管输入阻抗)的异常压力-流量关系，因为这些高流量器官非常容易受到脉动性损害；3)由此导致的脑血管和肾血管功能异常与脑和肾脏结构(MRI)和功能异常(认知测试、肾小球滤过率、蛋白尿)有关。我们的具体目标是：1)将中心脉压和外周脉压与主动脉结构和功能的详细测量联系起来。我们将使用磁共振成像技术，检测主动脉全长关键水平的主动脉直径、管壁厚度、僵硬度和血流，以全面评估主动脉功能各组成部分在脉压升高发病机制中的空间异质性贡献。2)探讨主动脉功能(动脉血压计)、脑血管输入阻抗与脑结构(定量MRI)和功能(标准化认知测试)之间的关系。我们将使用动脉血压计和总脑血流量对脑血管输入阻抗进行全面的无创性评估，并将在社区AGES-雷克雅未克研究的4000名参与者中将脑血管异常与脑结构和认知功能联系起来。3)主动脉和肾血管功能指标与肾脏结构和功能的关系。这项研究将为心血管疾病危险因素、脉压升高以及脑和肾功能随年龄增长而下降之间的关系提供关键的机制见解。公共卫生相关性：项目叙述主动脉僵硬异常和血压搏动性增加在60岁后非常普遍，并增加了心脏病、中风、痴呆症和肾脏疾病的风险。如果不采取措施预防或逆转老年人的主动脉僵硬，主动脉僵硬的高患病率、不良结局的高风险以及人口老龄化预示着可归因于主动脉功能异常的疾病负担的急剧增加。这项研究将确定导致主动脉僵硬的因素，并将确定异常僵硬对脑和肾脏的结构和功能的不利影响。

DESCRIPTION (provided by applicant): Aortic stiffness increases dramatically after 60 years of age and is associated with increased risk for heart disease, stroke, cognitive impairment and kidney disease. Although several risk factors for abnormal aortic stiffness have been identified, basic mechanisms in the causal pathway from risk factor to aortic dysfunction to excessive pressure pulsatility and downstream damage in the brain and kidney remain incompletely understood. Aortic stiffening and excessive blood pressure pulsatility are associated with microvascular remodeling, hypertrophy and impaired reactivity, which may contribute to end-organ damage. We propose to perform arterial tonometry and detailed magnetic resonance imaging (MRI) of the brain in 4000 participants and MRI of the aorta and kidneys in 600 participants in the Age, Gene/Environment Susceptibility- Reykjavik study (AGES-Reykjavik). Our hypotheses for this proposal are 3 fold: 1) that wall stiffening in the proximal aortic arch and mismatch between aortic diameter and flow are major sources of excessive pressure pulsatility in older people, 2) that the consequent increase in pulse pressure has detrimental effects on small vessel structure and function that manifest as abnormal pressure-flow relations in the brain (cerebrovascular input impedance) and kidneys (renovascular input impedance) because these high-flow organs are highly susceptible to pulsatile damage and 3) that the resulting abnormalities in cerebrovascular and renovascular function are associated with abnormal brain and kidney structure (MRI) and function (cognitive testing, glomerular filtration rate, albuminuria). Our specific aims are: 1) To relate central and peripheral pulse pressure to detailed measures of aortic structure and function. Using MRI, we will examine aortic diameter, wall thickness, stiffness and flow at key levels along the full length of the aorta in order to evaluate comprehensively the spatially heterogeneous contribution of each component of aortic function to the pathogenesis of increased pulse pressure. 2) To examine relations between aortic function (arterial tonometry), cerebrovascular input impedance and brain structure (quantitative MRI) and function (standardized cognitive testing). Using arterial tonometry and total brain blood flow, we will perform a comprehensive noninvasive assessment of cerebrovascular input impedance and will relate cerebrovascular abnormalities to brain structure and cognitive function in 4000 participants in the community-based AGES-Reykjavik study. 3) To relate measures of aortic and renovascular function to kidney structure and function. This study will provide critical mechanistic insights into the relations between cardiovascular disease risk factors, increased pulse pressure and declining brain and kidney function with advancing age. PUBLIC HEALTH RELEVANCE: Project Narrative Abnormal aortic stiffness and increased blood pressure pulsatility are highly prevalent after 60 years of age and convey increased risk of heart disease, stroke, dementia and kidney disease. The combination of high prevalence of aortic stiffness, high risk for an adverse outcome and aging of the population portends a dramatic increase in the burden of disease attributable to abnormal aortic function unless steps are taken to prevent or reverse aortic stiffening in older people. This study will identify factors that contribute to aortic stiffening and will define the adverse effects of abnormal stiffness on structure and function of brain and kidneys.